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The effect of maternal age on the risk of meiotic abnormality is well documented. In contrast little is known about the effect of the paternal age. The question of the risk related to paternal age is raised because of the increased demand of Assisted Reproduction Techniques for older men. This review focuses on the alterations of male semen parameters, testis histology and genetic risks related to age. The motility, vitality and morphology of spermatozoa and semen volume are found decreasing with age. Histomorphometric studies reveal various alterations including a thickening of the basal membrane when spermatogenesis is arrested. The number of germinal and Sertoli cells decreases with increased age. Up to 95 years old, we could find subjects with complete spermatogenesis. Chromosomal analyses in different studies have provided controversial results. Our investigation on subjects aged from 29 to 102 showed that the rate of aneuploidy in the group of aged subjects with preserved spermatogenesis was not statistically different from the young control group. However the incidence of postmeiotic aneuploidy was increased when spermiogenesis had stopped. On the other hand from epidemiological studies, autosomal dominant diseases are known to be associated with paternal age. However, in the case of achondroplasia and Apert syndrome, direct DNA sperm analysis did not reveal significant increase in the mutation frequency with paternal age.

Objective To investigate the endometrial immunohistochemical staining of interleukin (IL)-12 and IL-18 and to quantify the CD56 bright natural killer (NK) cells in relation to Doppler vascular disorders. Design Controlled clinical study. Setting Research unit of a university hospital. Patient(s) Thirty-five women with repeated implantation failure after ET in IVF and 12 fertile control patients. Intervention(s) Ultrasound evaluation and endometrial biopsy on day 20. Main outcome measure(s) The balance between IL-12 and IL-18, the number of NK cells, and the vascular status among fertile and implantation failure patients. Result(s) The control patients displayed normal vascular parameters, a weak anti–IL-12 staining, a consistent moderate stromal anti–IL-18 staining, and fewer than 15 NK cells/field. This pattern was observed among only 17% (6/35) of the implantation failure group. The remaining patients fit into one of two patterns: [1] 37% (13/35) had more than 40 NK cells/field with a strong anti–IL-12 and/or anti–IL-18 staining, and [2] the remaining 46% (16/35) had a marked local depletion of IL-18 and IL-12. Respectively, 85% and 31% of two groups displayed abnormal vascular parameters. Conclusion(s) Distinctions between the different local dysregulations of the cytokine network may provide clues for further exploration and treatment.

Problem: Human in vitro fertilization (IVF) embryo transfer is accompanied by a low implantation rate even after a very successful IVF, and there are a certain number of ‘idiopathic sterilities’ which are due to repeated implantation failures. In the very same vein, the question of improving implantation rates is of prime importance in agricultural research to improve the management of livestock. Pre-implantation prenatal diagnosis cannot be accomplished in individuals who have a high rate of implantation failure, whether women undergoing IVF, or animals, during genetic cloning. Implantation cytokine networks need to be known in such a perspective. Methods: We review the evolution and theories in reproductive immunology, briefly deal with the complexity of implantation as a step by step developmental event, and then present some of our recent data in mice and human. Conclusions: We conclude that the T helper cell type 1/2 (Th1/Th2) paradigm, as useful as it has been to explain pregnancy, is no longer sufficient in view of the emerging complexity of the cytokine network at the materno-fetal interface. This is peculiarly true for implantation, which, as a step by step developmentally regulated process, involving inflammatory molecules, cannot fit into such a scheme.

BACKGROUND: The possibility that a specific cytokine profile could be detected in the ovaries of patients with polycystic ovarian syndrome (PCOS) was investigated. METHOD: Enzyme-linked immunosorbent assay (ELISA) or bioassays were used to assess the concentrations of leukaemia inhibitory factor (LIF), tumour necrosis factor, interleukin 11, gamma interferon, progesterone and oestradiol in follicular fluids from preovulatory follicles collected after ovarian stimulation from 15 PCOS patients, 15 infertile control patients with regular cycles, and 8 oocyte donors. RESULTS: LIF and progesterone concentrations were significantly lower in the follicular fluid of PCOS patients (LIF median: 265 pg/ml) compared with controls (LIF median: 816 pg/ml); LIF and progesterone follicular fluid concentrations were correlated (r = 0.720, P = 0.0001). The LH/FSH ratio was negatively correlated with LIF concentrations (r = - 0.714, P = 0.0075). Although the PCOS and control patients did not differ significantly in age, ovarian reserve or IVF indication, the implantation rate was significantly lower among the women with PCOS (IR = 9 versus 21%, P = < 0.01). CONCLUSION: The specific cytokine profile of the PCOS patients is probably related to the lower implantation rate since follicular fluid LIF appears to function as an embryotrophic agent.

Patients with a history of repeated and unexplained implantation failure after IVF-embryo transfer and a high uterine natural killer cell count during estrogen-progestin treatment may benefit from controlled natural IVF-ET.

In a brief introduction, this review states why the presence of immune cells at the interface poses problems for an immunologist (Medawar paradigm). Different types of placentation are then discussed, and the various interactions with leukocytes, the extreme being with the equids where a certain degree of 'attack' is often seen. The limits of animal models when dealing with the human situation are emphasized. It is then stated why the various phases of pregnancy are different, and an analysis made of the cellular movements at the implantation, peri-implantation, immediate post-implantation and resorption windows in rodents. Details of the cellular components involved are given, as are hints for the human situation. The Th1/Th2 paradigm is described, with clinical examples, and its limits. Thus, the newly appraised dual role of natural killer (NK) cells is discussed, with examples in rodents and in humans (pre-eclampsia, implantation failure, abortion systems). Clinical data on the IL-12 /IL-18/NK tripod and implantation failure in humans are detailed.

This review introduces the field of cytokines and implantation and then recalls the specialized role of the uterus and the notion of the ‘implantation window’. The role of inflammatory and angiogenic cytokines is presented, as well as the involvement of cytokines such as -interferons in corpus luteum maintenance in non-chorionic gonadotrophin-producing species. -Interferons are reviewed, before dealing with the more in depth analysis of cytokine networks in the pre- and peri-implantation uterus. The emerging involvement of cytokines in controlling uterine vascularization angiogenesis is reviewed, with emphasis on NK activating factors.

BACKGROUND: Most implantation failures after successful in vitro fertilization-embryo transfer (IVF-ET) result from inadequate uterine receptivity. There is currently no way to predict this receptivity. METHODS: We investigated whether the detection of interleukin-(IL)18 by ELISA in uterine luminal secretions might predict implantation failure. Secretions of 133 patients enrolled in our IVF-ET program were sampled by uterine flushing immediately before oocyte retrieval. We assessed the following outcomes: pregnancy rate, multiple pregnancy rate, and implantation rate per embryo transferred. RESULTS: Interleukin-18 was detected in the flushing fluid of 38 patients (28.6%). Although the two groups were comparable for all other characteristics (age, etiology, ovarian reserve, number of embryos transferred, quality of embryos), all outcome variables differed significantly. The pregnancy rate was 37.9% in the IL-18 - ve group and 15% in the IL-18 + ve group, the multiple pregnancy rate 27.7% and 0%, and the implantation rate per embryo transferred 19.4% and 6.7% (all comparisons, P = 0.02). Only embryos meeting good quality criteria were transferred to 65 patients: 50 IL-18 - ve and 15 IL-18 + ve. The pregnancy rate was 51 % for the IL-18 - ve group and 20% for the IL-18 + ve group, the multiple pregnancy rate 36% and 0.0%, respectively, and the implantation rate 29% and 8.3% (P = 0.02). CONCLUSION: This non-invasive and simple method predicted inadequate uterine receptivity, independent of embryo quality.

Objective To document in the endometrium the correlation among the interleukin (IL)-12, -15, and -18 mRNA and the correlation between cytokine levels, vascular status, and endometrial natural killer (NK) cell count in the context of recurrent implantation failure. Design A pilot study. Setting Department of Reproductive Immunology. Patient(s) Women who failed to become pregnant after repeated IVF-embryo transfer and fertile control subjects. Intervention(s) Ultrasonic evaluation and endometrial biopsy in luteal phase. Main outcome measure(s) Uterine artery Doppler, count of uterine CD56 bright cells/field, and quantification by real-time polymerase chain reaction (PCR) to monitor IL-12 family (IL-12p40, IL-12p35, EBI3, IL-23), the IL-18 system (IL-18, IL-18R, IL18BP), and the IL-15 mRNA ratio. Result(s) The uterine artery Doppler and the CD56 bright cell counts were significantly different in fertile and infertile patients. The mean uterine artery pulsatility index correlated significantly negatively with the IL-18/actin ratio suggesting a defect of the cytokine-dependent vascular remodeling pathway. The number of uterine CD56 bright cells was significantly correlated with the IL-15/actin and IL-18/IL-18BP ratios. Thus, IL-18 and IL-15 seems to be involved in the local recruitment and the activation of uterine natural killer (uNK) cells. IL-18 was itself correlated with IL-15 and IL-12, suggesting a local control of uNK cells activation. Conclusion(s) The assessment of the tripod IL-12/-15/-18 shows distinct immune-related mechanisms that are involved in the broader context of inadequate uterine receptivity.

Background There is strong evidence that locally secreted cytokines control the implantation process and can cause implantation failure. Uterine flushing fluids were analysed to determine their concentrations of leukaemia inhibitory factor (LIF) and tumour necrosis factor (TNF). Methods and results We began by flushing the uterine cavities of 33 infertile patients on day 26 of two consecutive cycles. The concentrations of LIF (by enzyme-linked immunosorbent assay) and TNF (by bioassay) were significantly correlated during these cycles (r = 0.762, P = 0.0001 and r = 0.822, P = 0.001 respectively) and hence reliable. Then, after a reference flushing of 30 infertile patients, we followed the outcome of their first consecutive cycle of ovarian stimulation, which preceded either IVF or intrauterine insemination. A total of 10 patients became pregnant. The median concentration of LIF was 0 pg/ml (range: 0-177) and of TNF was 0 U/ml (range: 0-6.17) among those who became pregnant, and 203 pg/ml (range: 0-1620) and 2.14 U/ml (range: 0-16) respectively among those who did not. The LIF concentration was significantly lower in the pregnant group (P = 0.0013). Conclusion A low concentration of LIF in the uterine flushing fluid at day 26 was predictive of subsequent implantation. Use of this procedure should increase the number of IVF attempts yielding successful pregnancies and also lead to corrective therapies.